The present invention relates to methods for the preparation of biphenyl isoxazole sulfonamides and intermediates thereof. The present invention also relates to the novel intermediates prepared by these methods. The biphenyl isoxazole sulfonamides prepared by the present methods are endothelin antagonists useful, inter alia, for the treatment of hypertension.
The present methods allow preparation of biphenyl sulfonamides of the following formula I: 
where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups, enantiomers and diastereomers, and salts, preferably pharmaceutically acceptable salts, thereof. Preferred substituent groups for the biphenyl group include those groups R11 to R14 described herein and especially, when the biphenyl group is a 2-biphenyl group, the group 
in the 4xe2x80x2-position. Preferred methods of the present invention allow preparation of compounds of the following formula Ia: 
enantiomers and diastereomers, and salts, preferably pharmaceutically acceptable salts, thereof. Throughout this specification, the above symbols are defined as follows:
one of X and Y is N and the other is O;
R1, R2, R3 and R4 are each directly bonded to a ring carbon and are each independently
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1, Z2 and Z3;
(c) halo;
(d) hydroxyl;
(e) cyano;
(f) nitro;
(g) xe2x80x94C(O)H or xe2x80x94C(O)R5;
(h) xe2x80x94CO2H or xe2x80x94CO2R5;
(i) xe2x80x94Z4xe2x80x94NR6R7;
(j) xe2x80x94Z4xe2x80x94N(R10)xe2x80x94Z5xe2x80x94NR8R9; or
(k) R3 and R4 together may also be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached;
R5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
R6, R7, R8, R9 and R10 are each independently
(a) hydrogen; or
(b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3; or
R6 and R7 together may be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; or any two of R8, R9 and R10 together are alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
R11, R12, R13 and R14 are each independently
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1, Z2 and Z3,
(c) heterocycle, substituted heterocycle or heterocyclooxy;
(d) halo;
(e) hydroxyl;
(f) cyano;
(g) nitro;
(h) xe2x80x94C(O)H or xe2x80x94C(O)R5;
(i) xe2x80x94CO2H or xe2x80x94CO2R5;
(j) xe2x80x94SH, xe2x80x94S(O)nR5, xe2x80x94S(O)mxe2x80x94OH, xe2x80x94S(O)mxe2x80x94OR5, xe2x80x94Oxe2x80x94S(O)mxe2x80x94OR5, xe2x80x94Oxe2x80x94S(O)mOH or xe2x80x94Oxe2x80x94S(O)mxe2x80x94OR5;
(k) xe2x80x94Z4xe2x80x94NR6R7; or
(l) xe2x80x94Z4xe2x80x94N(R10)xe2x80x94Z5xe2x80x94NR8R9;
Z1, Z2 and Z3 are each independently
(a) hydrogen;
(b) halo;
(c) hydroxy;
(d) alkyl;
(e) alkenyl;
(f) aryl;
(g) aralkyl;
(h) alkoxy;
(i) aryloxy;
(j) aralkoxy;
(k) heterocycle, substituted heterocycle or heterocyclooxy;
(l) xe2x80x94SH, xe2x80x94S(O)nZ6, xe2x80x94S(O)mxe2x80x94OH, xe2x80x94S(O)mxe2x80x94OZ6, xe2x80x94Oxe2x80x94S(O)mxe2x80x94Z6, xe2x80x94Oxe2x80x94S(O)mOH or xe2x80x94Oxe2x80x94S(O)mxe2x80x94OZ6;
(m) oxo;
(n) nitro;
(o) cyano;
(p) xe2x80x94C(O)H or xe2x80x94C(O)Z6;
(q) xe2x80x94CO2H or xe2x80x94CO2Z6;
(r) xe2x80x94Z4xe2x80x94NZ7Z8;
(s) xe2x80x94Z4xe2x80x94N(Z11)xe2x80x94Z5xe2x80x94H;
(t) xe2x80x94Z4xe2x80x94N(Z11)xe2x80x94Z5xe2x80x94Z6; or
(u) xe2x80x94Z4xe2x80x94N(Z11)xe2x80x94Z5xe2x80x94NZ7Z8;
Z4 and Z5 are each independently
(a) a single bond;
(b) xe2x80x94Z9xe2x80x94S(O)nxe2x80x94Z10xe2x80x94;
(c) xe2x80x94Z9xe2x80x94C(O)xe2x80x94Z10xe2x80x94;
(d) xe2x80x94Z9xe2x80x94C(s)xe2x80x94Z10xe2x80x94;
(e) xe2x80x94Z9xe2x80x94Oxe2x80x94Z10xe2x80x94;
(f) xe2x80x94Z9xe2x80x94Sxe2x80x94Z10xe2x80x94;
(g) xe2x80x94Z9xe2x80x94Oxe2x80x94C(O)xe2x80x94Z10xe2x80x94; or
(h) xe2x80x94Z9xe2x80x94C(O)xe2x80x94Oxe2x80x94Z10xe2x80x94;
Z6 is alkyl; alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy; alkenyl; alkynyl; cycloalkyl; cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl; cycloalkyl to which is fused a benzene ring; aryloxy substituted with one or two halogens; cycloalkylalkyl; cycloalkenyl; cycloalkenylalkyl; aryl; aryl substituted with methylenedioxy or one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy and trihaloalkoxy; or heterocycle or substituted heterocycle;
Z7 and Z8 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;
Z9 and Z10 are each independently a single bond, alkylene, alkenylene or alkynylene;
Z11 is
(a) hydrogen; or
(b) alkyl, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl;
or any two of Z7, Z8 and Z11 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
J is O, S, N or NR15;
K and L are N or C, provided that at least one of K or L is C;
R15 is hydrogen, alkyl, hydroxyethoxy methyl or methoxyethoxy methyl;
each m is independently 1 or 2;
each n is independently 0, 1 or 2; and
p is 0 or an integer from 1 to 2.
In accordance herewith, a compound of the formula I or salt thereof may be prepared by a method comprising the steps of:
(a) contacting a pinacol ester of the formula II or salt thereof: 
where the phenyl ring of said formula II may be further substituted, such as with one or more groups described for the groups R11 to R14 herein, with a halophenyl compound of the formula III or salt thereof: 
where the phenyl ring of said formula III may be further substituted, such as with one or more groups described for the groups R11 to R14 herein, and especially, when the biphenyl group of said compound of the formula I or salt thereof is a 2-biphenyl, the group 
para to the halo group, in the presence of a palladium(0) catalyst and, preferably, a base, to form a nitrogen-protected compound of the formula IV or salt thereof: 
where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups; and
(b) deprotecting the nitrogen of said compound of the formula Iv or salt thereof to form said compound of the formula I or salt thereof.
xe2x80x9cProtxe2x80x9d, as used in formula II and throughout this specification, denotes a nitrogen-protecting group, which may be any suitable nitrogen-protecting group such as 2-ethoxyethyl, 2-methoxypropyl, methoxyethoxymethyl or those described in European Patent Application Publication No. 569;193 (1993), incorporated herein by reference, and is preferably methoxyethoxymethyl (xe2x80x9cMEMxe2x80x9d). The halo group in formula III is preferably bromo or iodo, most preferably iodo.
In a preferred embodiment, a compound of the formula Ia or salt thereof may be prepared by a method comprising the steps of:
(a) contacting a pinacol ester of the formula IIa or salt thereof: 
xe2x80x83with a halophenyl compound of the formula IIIa or salt thereof: 
xe2x80x83in the presence of a palladium(0) catalyst and, preferably, a base, to form a nitrogen-protected compound of the formula IVa or salt thereof: 
(b) deprotecting the nitrogen of said formula IVa compound or salt thereof to form said compound of the formula Ia or salt thereof.
The present methods for preparing a compound of the formula I or salt thereof are advantageous in that they provide high yields with minimal or no formation of impurities.
Further provided herewith are novel intermediates of the present methods, and novel methods for preparing such intermediates.
The present invention is described further as follows. Listed below are definitions of terms used in this specification. These definitions apply to the terms as used throughout this specification, individually or as part of another group, unless otherwise indicated in specific instances.
The term xe2x80x9calkylxe2x80x9d or xe2x80x9calky-xe2x80x9d refers to straight or branched chain hydrocarbon groups having 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms. The expression xe2x80x9clower alkylxe2x80x9d refers to alkyl groups of 1 to 4 carbon atoms.
The term xe2x80x9calkoxyxe2x80x9d refers to alkyl-Oxe2x80x94.
The term xe2x80x9carylxe2x80x9d or xe2x80x9car-xe2x80x9d refers to phenyl, naphthyl and biphenyl.
The term xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 10 carbon atoms having at least one double bond. Groups of two to four carbon atoms are preferred.
The term xe2x80x9calkynylxe2x80x9d refers to straight or branched chain groups of 2 to 10 carbon atoms having at least one triple bond. Groups of two to four carbon atoms are preferred.
The term xe2x80x9calkylenexe2x80x9d refers to a straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., xe2x80x94(CH2)xxe2x80x94 wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.
The term xe2x80x9calkenylenexe2x80x9d refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkenylene groups are xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2CHxe2x95x90CHxe2x80x94 and xe2x80x94CH(C2H5)xe2x80x94CHxe2x95x90CHxe2x80x94.
The term xe2x80x9calkynylenexe2x80x9d refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylene groups are xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH(CH3)xe2x80x94Cxe2x89xa1Cxe2x80x94 and xe2x80x94Cxe2x89xa1Cxe2x80x94CH(C2H5)CH2xe2x80x94.
The term xe2x80x9calkanoylxe2x80x9d refers to groups of the formula xe2x80x94C(O)alkyl.
The terms xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9ccycloalkenylxe2x80x9d refer to cyclic hydrocarbon groups of 3 to 8 carbon atoms.
The term xe2x80x9chydroxyalkylxe2x80x9d refers to an alkyl group including one or more hydroxy radicals such as xe2x80x94CH2CH2OH, xe2x80x94CH2CH2OHCH2OH, xe2x80x94CH(CH2OH)2 and the like.
The terms xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d refer to fluorine, chlorine, bromine and iodine.
The terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclicxe2x80x9d and xe2x80x9cheterocycloxe2x80x9d refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and the like.
Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like.
Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The expression xe2x80x9csubstituted heterocyclexe2x80x9d refers to a heterocycle substituted with 1, 2 or 3 of the following:
(a) alkyl, especially lower alkyl;
(b) hydroxy (or protected hydroxy);
(c) halo;
(d) oxo (i.e. =O);
(e) amino, alkylamino or dialkylamino;
(f) alkoxy;
(g) carbocyclo, such as cycloalkyl;
(h) carboxy;
(i) heterocyclooxy;
(j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl;
(k) carbamyl, alkylcarbamyl or dialkylcarbamyl;
(l) mercapto;
(m) nitro;
(n) cyano;
(o) carboalkoxy;
(p) sulfonamido, sulfonamidoalkyl or sulfonamidodialkyl; 
(s) aryl;
(t) alkylcarbonyloxy;
(u) arylcarbonyloxy;
(v) arylthio;
(w) aryloxy;
(x) alkylthio;
(y) formyl;
(z) arylalkyl; or
(axe2x80x2) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, halo or trihaloalkyl.
The term xe2x80x9cheterocyclooxyxe2x80x9d denotes a heterocyclic group bonded through an oxygen bridge.
Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.
The compounds of formula I and intermediates thereof may form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolating or purifying the compounds of this invention.
The compounds of formula I and intermediates thereof may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, t-butyl amine, benzathine, N-methyl-D-glucamide and hydrabamine, and with amino acids such as arginine, lysine and the like. Such salts may be obtained by reacting these compounds with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by lyophilization.
When groups such as the R1 to R4 or R11 to R14 substituents comprise a basic moiety, such as amino or substituted amino, the compounds of formula I and intermediates thereof may form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrochloric acid, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, maleic acid, benzenesulfonate, toluenesulfonate and various other sulfonates, nitrates, phosphates, borates, acetates, tartrates, maleates, citrates, succinates, benzoates, ascorbates, salicylates and the like. Such salts may be formed by reacting these compounds in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by lyophilization.
In addition, when groups such as the R1 to R4 or R11 to R14 substituents comprise a basic moiety such as amino, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed.
Certain groups such as the R1 to R4 and R11 to R14 substituents of the compounds of the invention may contain asymmetric carbon atoms. The compounds of the invention such as those of the formula I and salts thereof may exist, therefore, in enantiomeric and diastereomeric forms and in racemic mixtures thereof. All are within the scope of this invention. Additionally, compounds such as those of formula I and salts thereof may exist as enantiomers even in the absence of asymmetric carbons. All such enantiomers are within the scope of this invention.
U.S. patent application Ser. No. 08/493,331, filed Jul. 24, 1995 (Attorney Docket No. HA662c) by Murugesan et al. and continuation-in-part thereof U.S. patent application Ser. No. 08/603,975, filed Feb. 20, 1996 (Attorney Docket No. HA662d) by Murugesan et al., entitled xe2x80x9cSubstituted Biphenyl Isoxazole Sulfonamidesxe2x80x9d, describing endothelin antagonists, starting materials and methods, are each incorporated herein by reference in its entirety.
A compound of the formula I or salt thereof may be prepared by coupling a pinacol ester of the formula II or salt thereof with a halophenyl compound of the formula III or salt thereof, and by deprotecting the nitrogen-protected compound IV or salt thereof formed by the aforementioned coupling.
Coupling of compounds of the formulae II and III or salts thereof is conducted in the presence of a palladium(0) catalyst, preferably palladium acetate/triphenylphosphine or other palladium (II) salt/triphenylphosphine, tetrakisphenylphosphine palladium or tris(dibenzylideneacetone)dipalladium, and, preferably, a base, preferably aqueous potassium carbonate or sodium carbonate, to form a nitrogen-protected compound of the formula IV or salt thereof. The preferred molar ratio of palladium (II) salt to triphenylphosphine is between 1:1 and 1:3. See the conditions for catalysis described by A. Suzuki et al., Pure and Applied Chemistry, 63, 419-422 (1991); A. Martin et al., Acta. Chem. Scand., 47, 221 (1993); H. Jendralla et al., Liebig Ann., 1253 (1995), all incorporated herein by reference.
When the halophenyl compound III is a compound IIIa, protection of the heteroatoms J and K or L may be desirable, in certain instances, to facilitate the coupling reaction. For example, when J and K or L are N, one of the groups may be protected by a suitable protecting group such as t-butoxycarbonyl, etc. Specific R11-R14 groups may be chosen to be compatible with the reaction conditions. Additionally, specific R11-R14 groups may be converted into alternative R11-R14 groups, either before or after coupling, using any suitable methods such as those known in the art.
The coupling method is preferably conducted at a temperature of from about 25xc2x0 C. to about 100xc2x0 C. (most preferably from about 45xc2x0 C. to about 75xc2x0 C.), at a pressure of about 1 atm, and under an atmosphere of argon or nitrogen. Molar ratios of the pinacol ester II or salt thereof to the halophenyl compound III or salt thereof are preferably from about 1:1 to about 1:1.2. Amounts of palladium(0) catalyst and base are selected to catalyze the coupling reaction and are preferably from about 2.5 mol % to about 10 mol %, and from about 2.5 equivalents to about 7 equivalents, respectively. Solvents are preferably employed which are selected from aqueous or organic liquids such as acetone, ethanol, toluene, tetrahydrofuran, dimethoxyethane and water, or mixtures thereof, preferably a mixture of toluene and ethanol. Amounts of solvent are preferably those wherein the pinacol ester II or salt thereof is from about 4 to about 9% by weight, based on the combined weight of solvent and pinacol ester II or salt thereof. For example, the following are exemplary ranges for solvent/pinacol ester II/base: tetrahydrofuran (30 to 70 mL), toluene (100 to 200 mL), ethanol (80 to 160 mL)/pinacol ester II (15 to 20 g)/aqueous 2M sodium carbonate (100 to 150 mL).
Residual palladium catalyst is preferably removed, either before or after deprotection of the compound of formula Iv or salt thereof, by contact with a chelating agent such as trithiocyanuric acid (xe2x80x9cTMTxe2x80x9d). Crystallization providing a suitable crystalline form of the compound of the formula I or salt thereof, subsequent to deprotection of the compound of the formula IV or salt thereof, is also contemplated by the present invention. Preferably, crystallization is achieved from a supersaturated ethanolic solution, with or without the presence of co-Solvents such as heptane or water, especially where seeded with the desired crystalline form. Most preferably, crystallization is conducted by the methods of the Examples herein.
Compounds of the formula III and salts thereof may be prepared by methods analogous to those described in U.S. patent application Ser. No. 08/493,331 and the aforementioned continuation-in-part thereof. Preferably, oxazole compounds of the formula IIIa or salts thereof are prepared by the novel methods for their preparation described herein. Compounds of the formula II and salts thereof are preferably prepared by the novel methods for their preparation described herein.
Deprotection of the formula IV compound or salt thereof formed by the present coupling method may be conducted by any suitable method, such as methods analogous to those described in U.S. patent application Ser. No. 08/493,331 and the aforementioned continuation-in-part thereof. Preferably, when xe2x80x9cprotxe2x80x9d is MEM, deprotection is conducted by heating in a mixture of aqueous HCl and ethanol.
The pinacol esters of the formula II and salts thereof may themselves be formed by novel methods provided herein. In accordance herewith, a pinacol ester of the formula II or salt thereof may be prepared by a method comprising the steps of:
(a) contacting a compound of the formula V or salt thereof: 
where the phenyl group of said formula v may be further substituted, such as with one or more groups described for the groups R11 to R14 herein, and where halo is preferably bromo, chloro or iodo, most preferably bromo, with an amine of the formula VI or salt thereof: 
xe2x80x83in the presence of an organic base and an organic solvent, to form a compound of the formula VII or salt thereof: 
xe2x80x83where the phenyl group of said formula VII may be further substituted, such as with one or more groups described for the groups R11 to R14 herein;
(b) protecting the nitrogen of said compound of the formula VII or salt thereof to form a compound of the formula VIII or salt thereof: 
xe2x80x83where the phenyl group of said formula VIII may be further substituted, such as with one or more groups described for the groups R11 to R14 herein;
(c) lithiating said compound of the formula VIII or salt thereof with an alkyl or aryl lithium compound and contacting the lithiated product formed with a trialkylborate, followed by hydrolysis, to form a boronic acid of the formula IX or salt thereof: 
xe2x80x83where the phenyl group of said formula IX may be further substituted, such as with one or more groups described for the groups R11 to R14 herein; and
(d) contacting said compound of the formula IX or salt thereof with pinacol (i.e., 2,3-dimethyl-2,3-butanediol), with removal of water, thereby forming said compound of the formula II or salt thereof.
In a preferred embodiment, a pinacol ester of the formula IIa or salt thereof may be prepared by a method comprising the steps of:
(a) contacting a compound of the formula Va or salt thereof: 
xe2x80x83with an amine of the formula VIa or salt thereof: 
xe2x80x83in the presence of an organic base and organic solvent, to form a compound of the formula VIIa or salt thereof: 
(b) protecting the nitrogen of said compound of the formula VIIa or salt thereof to form a compound of the formula VIIIa or salt thereof: 
(c) lithiating said compound of the formula VIIIa or salt thereof with an alkyl or aryl lithium compound and contacting the lithiated product formed with a trialkylborate, followed by hydrolysis, to form a boronic acid of the formula IXa or salt thereof: 
(d) contacting said compound of the formula IXa or salt thereof with pinacol, with removal of water, thereby forming said compound of the formula IIa or salt thereof.
The term xe2x80x9cleaving groupxe2x80x9d, as used herein, denotes any suitable leaving group such as a halo group, preferably chloro. Any suitable organic base may be employed in step (a). Preferred organic bases include amines such as pyridine or a trialkylamine. The organic solvent employed in step (a) is preferably a haloalkane, such as dichloromethane or 1,2-dichloroethane, or the organic base, such as neat pyridine, may also function as the solvent.
As described above, compounds of the formula VIII and salts thereof may be prepared by contacting a compound of the formula V or salt thereof with an amine compound of the formula VI or salt thereof, and by protecting the nitrogen of the product compound VII or salt thereof. The formula VIII compound or salt thereof obtained is then lithiated with an alkyl or aryl lithium compound, preferably with n-butyl lithium or phenyl lithium, at temperatures which are preferably from about xe2x88x9240xc2x0 C. to about xe2x88x92105xc2x0 C. (especially, from about xe2x88x9270xc2x0 C. to about xe2x88x92100xc2x0 C.), to form the compound: 
where the phenyl group of said compound may be further substituted, such as with one or more groups described for the groups R11 to R14 herein, or salt thereof, preferably the compound: 
or salt thereof. Treatment of the lithiated compound or salt thereof with a trialkylborate such as triisopropylborate or, preferably, trimethylborate, at temperatures which are preferably from about xe2x88x9240xc2x0 C. to about xe2x88x92105xc2x0 C. (especially, from about xe2x88x9270xc2x0 C. to about xe2x88x92100xc2x0 C.), provides the following boronate ester: 
where the phenyl group of said compound may be further substituted, such as with one or more groups described for the groups R11 to R14 herein, or salt thereof, preferably the boronate ester: 
or salt thereof, which may then be hydrolyzed with a suitable acid, preferably an aqueous acid such as aqueous hydrochloric acid, or with a suitable base, to form the boronic acid IX or salt thereof. The hydrolysis step, forming the boronic acid IX or salt thereof, is advantageous as the boronic acid possesses enhanced stability relative to the boronate ester from which it is obtained. The aforementioned steps may be conducted by methods analogous to those described in, and with starting materials of the formulae V and VI and salts thereof prepared by methods analogous to those described in, European Patent Application Publication No. 569,193 (1993) and in U.S. patent application Ser. No. 08/493,331 and the aforementioned continuation-in-part thereof.
The boronic acid IX or salt thereof may then be contacted with pinacol, with the removal of water, to form the corresponding pinacol ester II or salt thereof. Removal of water may be conducted, for example, by the addition of a drying agent such as magnesium sulfate or by azeotropic removal of water by heating with a solvent such as toluene. This reaction is preferably conducted at a temperature of from about 110xc2x0 C. to about 120xc2x0 C. (most preferably from about 112xc2x0 C. to about 115xc2x0 C.), at a pressure of about 1 atm, and under an atmosphere of argon or nitrogen. Molar ratios of pinacol to the boronic acid IX or salt thereof are preferably from about 1:1 to about 1.1:1. Solvents are preferably employed which are selected from organic liquids such as toluene. Amounts of solvent are preferably those wherein the boronic acid IX or salt thereof is from about 4 to about 10% by weight, based on the combined weight of solvent and boronic acid IX or salt thereof.
The boronic acid IX or salt thereof (preferably, the preferred boronic acid IXa or salt thereof) may be directly coupled with the halophenyl compound III or salt thereof to form a formula IV compound or salt thereof. This method, especially where the halophenyl compound III or salt thereof is an iodophenyl compound III or salt thereof (preferably, an iodophenyl compound IIIa or salt thereof), is also contemplated by the present invention. The pinacol ester II or salt thereof in place of the boronic acid IX or salt thereof may be advantageous, however, as the pinacol ester compounds are highly stable, and lesser amounts of impurities may be formed and higher yields of the formula IV compound or salt thereof may be obtained upon coupling with a halophenyl compound III or salt thereof.
Halophenyl compounds of the formula III and salts thereof may be prepared by methods analogous to those described in U.S. patent application Ser. No. 08/493,331 and the aforementioned continuation-in-part thereof. Preferred compounds of the formula IIIa and salts thereof bearing an oxazole ring may also be formed by novel methods provided herein. In accordance herewith, a formula IIIa(1) oxazole or salt thereof may be prepared by a method comprising the steps of:
(a) contacting a phenyl acid halide X or salt thereof: 
xe2x80x83with an amine acetal XI or salt thereof: 
xe2x80x83in the presence of a base and a solvent, to form an amide acetal of the formula XII or salt thereof: 
(b) cyclizing the amide acetal of the formula XII or salt thereof, in the presence of a cyclization agent, to form an oxazole phenyl halide of the formula IIIa(1) or salt thereof: 
The starting phenyl acid halide X or salt thereof is commercially available or may readily be prepared by one of ordinary skill in the art. The halo group of the acid halide moiety is preferably chloro; the halo group in the position para to the acid halide moiety is preferably bromo, chloro, or iodo, most preferably iodo. The starting amine acetal XI or salt thereof is also commercially available or may readily be prepared by one of ordinary skill in the art. The alkyl groups of the acetal moiety are preferably methyl or ethyl, most preferably, methyl.
The base employed in step (a) may be any suitable base, and is preferably an alkali metal carbonate, bicarbonate or hydroxide, most preferably, potassium bicarbonate (in a solvent such as water and/or acetone) or potassium carbonate (in a solvent such as methylene chloride).
Cyclization is conducted by contacting the amide acetal XII or salt thereof with a cyclization agent which may be any compound effecting the cyclization reaction, and is preferably Eaton""s reagent (i.e., methanesulfonic acid and phosphoric oxide) or polyphosphoric acid (PPA), most preferably Eaton""s reagent. The cyclization is preferably conducted at a temperature of from about 125xc2x0 C. to about 150xc2x0 C. (most preferably from about 130xc2x0 C. to about 135xc2x0 C.), at a pressure of about 1 atm, and under an atmosphere of argon or nitrogen. Amounts of cyclization agent are selected to achieve cyclization and are preferably from about (catalyst/substrate) 8 mL/g to about 15 mL/g when Eaton""s reagent is employed. Eaton""s reagent is a solution of P2O5 in methanesulfonic acid and can also function as a preferred solvent for the cyclization. Exemplary compositions for Eaton""s reagent are those containing 7.5 to 15% by weight P2O5 in methanesulfonic acid.
The compounds of the formula IIIa and salts thereof may also be used in a further method (xe2x80x9creverse couplingxe2x80x9d) contemplated by the present invention, for the preparation of compounds of the formula Ia or salts thereof, comprising the steps of:
(a) lithiating a compound of the formula IIIa or salt thereof: 
xe2x80x83preferably, a compound of the formula IIIa(1) or salt thereof, with an alkyl or aryl lithium compound in the presence of a trialkylborate, followed by hydrolysis, to form a boronic acid of the formula XIII or salt thereof: 
(b) contacting the boronic acid of the formula XIII or salt thereof with a compound of the formula VIIIa or salt thereof: 
xe2x80x83where halo is preferably bromo, iodo or chloro, most preferably bromo, in the presence of a palladium(0) catalyst and, preferably, a base, to form a nitrogen-protected compound of the formula IVa or salt thereof: 
(c) deprotecting the nitrogen of said formula IVa compound or salt thereof to form said compound of the formula Ia or salt thereof.
With respect to this method, lithiation is conducted in the presence of a trialkylborate, followed by hydrolysis which may be conducted under conditions as described herein for the preparation of boronic acids of the formula IX and salts thereof. Coupling in the presence of a palladium(0) catalyst and, preferably, base, and deprotection of the nitrogen-protected coupled product, may be conducted under conditions as described herein for the coupling of compounds of the formulae II and III and salts thereof, and deprotection of the product thereof. Lithiation provides a compound having the following structure or a salt thereof: 
xe2x80x83contact with a trialkylborate provides the following boronate ester or a salt thereof: 
It is preferred that the compounds employed in or prepared by the present methods contain one or more, preferably all where appropriate, of the following substituents:
X is O and N is Y;
the ring bearing K, L and J is 2-oxazole;
p is zero;
R1 and R2 are each independently hydrogen, alkyl, alkoxy, aryl, hydroxyalkyl, xe2x80x94CO2R5 or xe2x80x94Z4xe2x80x94NR6R7, most preferably lower alkyl or hydrogen;
R3 and R4 are each independently alkyl, most preferably lower alkyl, especially methyl; and
R11, R12, R13 and R14 are each independently hydrogen, hydroxy, amino, heterocyclo, alkenyl, alkoxy, carboxamide or substituted lower alkyl, most preferably, R12 to R14 are hydrogen and R11 is hydrogen, hydroxy, amino, heterocyclo, alkenyl, alkoxy, carboxamide or substituted lower alkyl.
Compounds of interest include those, inter alia, wherein at least one of (i) to (iv) applies: (i) at least one of R11, R12, R13 or R14 is heterocycle, substituted heterocycle or heterocyclooxy; (ii) at least one of Z1, Z2 or Z3 is aryl, heterocycle, substituted heterocycle or heterocyclooxy; (iii) Z6 is alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy, wherein at least one substituent is other than aryl; alkyl substituted with two or three aryl groups; cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl; cycloalkyl to which is fused a benzene ring; aryloxy substituted with one or two halogens; aryl substituted with methylenedioxy; aryl substituted with one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy and trihaloalkoxy; or heterocycle or substituted heterocycle; or (iv) Z11 is alkyl substituted with one, two or three halogens.
The compounds of the formula I and salts thereof are antagonists of ET-1, ET-2 and/or ET-3 and are useful in treatment of conditions associated with increased ET levels (e.g., dialysis, trauma and surgery) and of all endothelin-dependent disorders. They are thus useful as antihypertensive agents. By the administration of a composition having one (or a combination) of the compounds of this invention, the blood pressure of a hypertensive mammalian (e.g., human) host is reduced. They are also useful in pregnancy-induced hypertension and coma (preeclampsia and eclampsia), acute portal hypertension and hypertension secondary to treatment with erythropoietin.
The compounds of the present invention are also useful in the treatment of disorders related to renal, glomerular and mesangial cell function, including acute and chronic renal failure, glomerular injury, renal damage secondary to old age or related to dialysis, nephrosclerosis (especially hypertensive nephrosclerosis), nephrotoxicity (including nephrotoxicity related to imaging and contrast agents and to cyclosporine), renal ischemia, primary vesicoureteral reflux, glomerulosclerosis and the like. The compounds of this invention may also be useful in the treatment of disorders related to paracrine and endocrine function.
The compounds of the present invention are also useful in the treatment of endotoxemia or endotoxin shock as well as hemorrhagic shock.
The compounds of the present invention are also useful in hypoxic and ischemic disease and as anti-ischemic agents for the treatment of, for example, cardiac, renal and cerebral ischemia and reperfusion (such as that occurring following cardiopulmonary bypass surgery), coronary and cerebral vasospasm, and the like.
In addition, the compounds of this invention may also be useful as anti-arrhythmic agents; anti-anginal agents; anti-fibrillatory agents; anti-asthmatic agents; anti-atherosclerotic and anti-arteriosclerotic agents; additives to cardioplegic solutions for cardiopulmonary bypasses; adjuncts to thrombolytic therapy; and anti-diarrheal agents. The compounds of this invention may be useful in therapy for myocardial infarction; therapy for peripheral vascular disease (e.g., Raynaud""s disease and Takayashu""s disease); treatment of cardiac hypertrophy (e.g., hypertrophic cardiomyopathy); treatment of primary pulmonary hypertension (e.g., plexogenic, embolic) in adults and in the newborn and pulmonary hypertension secondary to heart failure, radiation and chemotherapeutic injury, or other trauma; treatment of central nervous system vascular disorders, such as stroke, migraine and subarachnoid hemorrhage; treatment of central nervous system behavioral disorders; treatment of gastrointestinal diseases such as ulcerative colitis, Crohn""s disease, gastric mucosal damage, ulcer and ischemic bowel disease; treatment of gall bladder or bile duct-based diseases such as cholangitis; treatment of pancreatitis; regulation of cell growth; treatment of benign prostatic hypertrophy; restenosis following angioplasty or following any procedures including transplantation; therapy for congestive heart failure including inhibition of fibrosis; inhibition of left ventricular dilatation, remodeling and dysfunction; and treatment of hepatotoxicity and sudden death. The compounds of this invention may be useful in the treatment of sickle cell disease including the initiation and/or evolution of the pain crises of this disease; treatment of the deleterious consequences of ET-producing tumors such as hypertension resulting from hemangiopericytoma; treatment of early and advanced liver disease and injury including attendant complications (e.g., hepatotoxicity, fibrosis and cirrhosis); treatment of spastic diseases of the urinary tract and/or bladder; treatment of hepatorenal syndrome; treatment of immunological diseases involving vasculitis such as lupus, systemic sclerosis, mixed cryoglobulinemia; and treatment of fibrosis associated with renal dysfunction and hepatotoxicity. The compounds of this invention may be useful in therapy for metabolic and neurological disorders; cancer; insulin-dependent and non insulin-dependent diabetes mellitus; neuropathy; retinopathy; maternal respiratory distress syndrome; dysmenorrhea; epilepsy; hemorrhagic and ischemic stroke; bone remodeling; psoriasis; and chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, sarcoidosis and eczematous dermatitis (all types of dermatitis).
The compounds of the formula I and salts thereof can also be formulated in combination with endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; thromboxane receptor antagonists; potassium channel openers; thrombin inhibitors (e.g., hirudin and the like); growth factor inhibitors such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; angiotensin II (AII) receptor antagonists; renin inhibitors; angiotensin converting enzyme (ACE) inhibitors such as captopril, zofenopril, fosinopril, ceranapril, alacepril, enalapril, delapril, pentopril, quinapril, ramipril, lisinopril and salts of such compounds; neutral endopeptidase (NEP) inhibitors; dual NEP-ACE inhibitors; HMG CoA reductase inhibitors such as pravastatin and mevacor; squalene synthetase inhibitors; bile acid sequestrants such as questran; calcium channel blockers; potassium channel activators; beta-adrenergic agents; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide or benzothiazide as well as ethacrynic acid, tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds; and thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase and anisoylated plasminogen streptokinase activator complex (APSAC). If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. The compounds of this invention may also be formulated with, or useful in conjunction with, antifungal and immunosuppressive agents such as amphotericin B, cyclosporins and the like to counteract the glomerular contraction and nephrotoxicity secondary to such compounds. The compounds of this invention may also be used in conjunction with hemodialysis.
The compounds of the invention can be administered orally or parenterally to various mammalian species known to be subject to such maladies, e.g., humans, in an effective amount within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) in single or 2 to 4 divided daily doses.
The active substance can be utilized in a composition such as tablet, capsule, solution or suspension containing about 5 to about 500 mg per unit dosage of a compound or mixture of compounds of formula I or in topical form for wound healing (0.01 to 5% by weight compound of formula I, 1 to 5 treatments per day). They may be compounded in a conventional manner with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc., or with a topical carrier such as Plastibase (mineral oil gelled with polyethylene) as called for by accepted pharmaceutical practice.
The compounds of the invention may also be administered topically to treat peripheral vascular diseases and as such may be formulated as a cream or ointment.
The compounds of formula I can also be formulated in compositions such as sterile solutions or suspensions for parenteral administration. About 0.1 to 500 milligrams of a compound of formula I is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
The present invention will now be further described by the following working examples, which illustrate preferred embodiments of the invention.